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Methods in Cell Biology 1978
Topics: Cell Division; Cell Nucleus; Plicamycin; Staining and Labeling; Yeasts
PubMed: 80736
DOI: 10.1016/s0091-679x(08)62015-4 -
Biopolymers Aug 2000Mithramycin and chromomycin, two antitumor drugs, each having an identical aglycone and nearly identical disaccharide and trisaccharide side chains, have differing...
Mithramycin and chromomycin, two antitumor drugs, each having an identical aglycone and nearly identical disaccharide and trisaccharide side chains, have differing binding properties to a small oligonucleotide, d(ACCCGGGT)(2) (M. A. Keniry et al., Journal of Molecular Biology, 1993, Vol. 231, pp. 753-767). In order to understand the forces that induce four mithramycin molecules to bind to d(ACCCGGGT)(2) instead of two drug molecules in the case of chromomycin, the structure of the 4:2:1 mithramycin: Mg(2+):d(ACCCGGGT)(2) complex was investigated by (1)H-nmr and restrained molecular dynamics. The resulting three-dimensional model showed that in order to accommodate the close approach of one neighboring mithramycin dimer, the inwardly directed CDE saccharide chain of the neighboring mithramycin dimer undergoes a conformational change such that the E saccharide no longer spans the minor groove but reorients so that the hydrophilic face of the E saccharides from the two dimers oppose each other. Two hydrogen bonds are formed between the hydroxyl groups of the two opposing E saccharide groups. The results are interpreted in terms of the differences in stereochemistry and functional group substitutions between mithramycin and chromomycin. A mithramycin dimer is able to self-associate on an oligonucleotide template because it has two hydroxyl groups on the same face of its terminal E saccharide. A chromomycin dimer is unable to self-associate because one of these hydroxyl groups is acetylated and the neighboring hydroxyl group has a stereochemistry that cannot permit close contact of the hydroxyl group with a neighbouring chromomycin dimer.
Topics: Antibiotics, Antineoplastic; Dimerization; Hydrogen Bonding; Ligands; Magnesium; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Molecular Structure; Nonlinear Dynamics; Oligodeoxyribonucleotides; Plicamycin
PubMed: 10861371
DOI: 10.1002/1097-0282(200008)54:2<104::AID-BIP3>3.0.CO;2-2 -
Cancer Chemotherapy and Pharmacology Sep 2017In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to...
PURPOSE
In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma.
PATIENTS AND METHODS
Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis.
RESULTS
The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment.
CONCLUSIONS
Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.
Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Child; Female; Humans; Male; Oncogene Proteins, Fusion; Plicamycin; Proto-Oncogene Protein c-fli-1; RNA-Binding Protein EWS; Sarcoma, Ewing; Young Adult
PubMed: 28735378
DOI: 10.1007/s00280-017-3382-x -
FEBS Letters May 1990DNA fragments containing (AT)n inserts cloned adjacent to putative mithramycin binding sites have been examined by footprinting experiments using a variety of nucleases...
DNA fragments containing (AT)n inserts cloned adjacent to putative mithramycin binding sites have been examined by footprinting experiments using a variety of nucleases in the presence of the drug. The results demonstrate that mithramycin induces a DNA structural change which renders adjacent (AT)n sequences sensitive to attack by DNase II. Significant changes are also revealed with DNase I and micrococcal nuclease. The results are consistent with a model in which mithramycin opens the DNA minor groove changing it to a structure which is locally more like A-DNA.
Topics: Adenine; Base Composition; Base Sequence; Cloning, Molecular; Cytosine; DNA; Deoxyribonucleases; Guanine; Molecular Sequence Data; Nucleotide Mapping; Plasmids; Plicamycin; Thymine
PubMed: 2140099
DOI: 10.1016/0014-5793(90)80775-e -
Cancer Chemotherapy Reports Jul 1960
Topics: Anti-Bacterial Agents; Neoplasms; Plicamycin
PubMed: 13858517
DOI: No ID Found -
Lancet (London, England) Mar 1975The treatment of rapidly progressive skeletal demineralisation in myelomatosis has been studied with the help of metabolic calcium balance in two patients; In one,...
The treatment of rapidly progressive skeletal demineralisation in myelomatosis has been studied with the help of metabolic calcium balance in two patients; In one, osteoporosis accelerated during treatment with melphalan and prednisolone, although he remained normocalcaemic throughout, suggesting that osteoporosis was aggravated by corticosteroid therapy. In the other patient, who was initially hypercalcaemic, conventional treatment produced clinical remission before eventual relapse with more hypercalcaemia and skeletal dissolution. Both patients were then treated with mithramycin alone, and, although neither obtained haematological remission, bone pain was relieved, hypercalciuria and hypercalcaemia were abolished, and calcium balances proved that mithramycin was effective in restoring calcium equilibrium. The results indicate that mithramycin may abolish excessive bone resorption in myelomatosis and that severe bone dissolution may occur in the absence of hypercalcaemia. Regular determination of 24-hour urinary calcium excretion as well as of plasma-calcium is important in monitoring process. Mithramycin should be considered in the early treatment not only of hypercalcaemia but also of severe hypercalciuria, if these complications do not rapidly remit during the first course of conventional myeloma therapy, with or without steroids. Finally, these results add to evidence that a humoral factor may be responsible for osteoclast stimulation in myelomatosis.
Topics: Aged; Calcium; Cyclophosphamide; Drug Therapy, Combination; Female; Humans; Hypercalcemia; Injections, Intravenous; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteolysis; Phosphorus; Plicamycin; Prednisolone; Water-Electrolyte Balance
PubMed: 47484
DOI: 10.1016/s0140-6736(75)91631-1 -
Cancer Apr 1973
Topics: Adult; Bone Neoplasms; Female; Humans; Lung Neoplasms; Male; Neoplasm Metastasis; Plicamycin; Radiography; Remission, Spontaneous; Sarcoma, Ewing
PubMed: 4267530
DOI: 10.1002/1097-0142(197304)31:4<889::aid-cncr2820310419>3.0.co;2-h -
PloS One 2015Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding...
Demycarosyl-3D-ß-D-digitoxosyl-mithramycin SK (DIG-MSK) is a recently isolated analogue of mithramycin A (MTA) that showed differences with MTA in the DNA binding strength and selectivity. These differences correlated with a better therapeutic index and less toxicity in animal studies. Herein, we show that DIG-MSK displays a potent anti-tumor activity against different types of cancer cell lines, ovarian tumor cells being particularly sensitive to this drug. Of relevance, DIG-MSK exerts low toxicity on fibroblasts and peripheral blood mononuclear cells, this toxicity being significantly lower than that of MTA. In correlation with its antitumor activity, DIG-MSK strongly inhibited Sp1-mediated transcription and endogenous Sp1 mRNA expression, which correlated with the inhibition of the expression of key Sp1-regulated genes involved in tumorigenesis, including VEGFA, BCL2L1 (Bcl-XL), hTERT, BRCA2, MYC and SRC in several ovarian cells. Significantly, DIG-MSK was a stronger inhibitor of VEGFA expression than MTA. Accordingly, DIG-MSK also exhibited potent anti-angiogenic activity on microvascular endothelial cells. Likewise, it significantly inhibited the gene expression of VEGFR1, VEGFR2, FGFR, PDGFB and PDGFRA and, additionally, it induced the expression of the anti-angiogenic factors angiostatin and tunstatin. These effects correlated with a pro-apoptotic effect on proliferating microvascular endothelial cells and the inhibition of the formation of endothelial capillary structures. Overall, the pleiotropic activity of DIG-MSK in inhibiting key oncogenic and angiogenic pathways, together with its low toxicity profile, highlight the therapeutic potential of this new drug.
Topics: Angiogenesis Inducing Agents; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Female; G1 Phase Cell Cycle Checkpoints; Gene Expression Regulation, Neoplastic; Human Umbilical Vein Endothelial Cells; Humans; Leukocytes, Mononuclear; Neovascularization, Physiologic; Ovarian Neoplasms; Plicamycin; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2
PubMed: 26536461
DOI: 10.1371/journal.pone.0140786 -
Neuropharmacology 2011Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various neurodegenerative diseases. Although the underlying mechanisms of these diseases... (Comparative Study)
Comparative Study
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of various neurodegenerative diseases. Although the underlying mechanisms of these diseases have been suggested by many studies, therapeutic drugs have yet to be found. In this study, experiments were performed to examine the effect of mithramycin (MTM), a clinically approved guanosine-cytosine (GC)-rich DNA sequence-binding antitumor antibiotic, on ER stress-induced neurotoxicity in organotypic hippocampal slice cultures (OHCs). Time-dependent induction of the ER chaperones, glucose-regulated protein (GRP) 78 and GRP94, was observed after treatment with tunicamycin (TM) (80 μg/mL). Western blot analysis showed that treatment of OHCs with TM increased the expression of CHOP and the cleaved forms of caspase-12. Simultaneous application of MTM suppressed TM-induced cell death in all areas of OHCs with a concomitant decrease in the level of CHOP. In contrast, MTM had no effect on excitotoxic cell death induced by ibotenic acid, a potent N-methyl-d-aspartate (NMDA) agonist in OHCs. Moreover, RNA interference to CHOP or simultaneous treatment with MTM attenuated TM-induced cell death in primary cultured hippocampal neurons. These results suggest that CHOP plays a critical role in the mechanisms underlying ER-stress-induced neurotoxicity in the hippocampus, and that MTM could be a protective agent against ER stress-induced hippocampal neuronal death through attenuation of ER stress-associated signal proteins.
Topics: Animals; Cell Death; Cells, Cultured; Endoplasmic Reticulum; Hippocampus; Neuroprotective Agents; Organ Culture Techniques; Oxidative Stress; Plicamycin; Rats; Rats, Wistar; Tunicamycin
PubMed: 21527262
DOI: 10.1016/j.neuropharm.2011.04.009 -
Presbyterian-St. Luke's Hospital... Jan 1963
Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Antineoplastic Agents; Dermatologic Agents; Humans; Neoplasm Metastasis; Neoplasms; Plicamycin
PubMed: 14034164
DOI: No ID Found